Stable sulpho-adenosyl-L-methionine (SAMe) salts, particularly suitable for parenteral use

ABSTRACT

The present invention relates to new stable sulpho-adenosyl-L-methionine (SAMe) salts particularly suitable for parenteral use, their production process, and pharmaceutical compositions containing them as active principles. 
     Said salts correspond to the general formula: 
     
         SAMe.n(CH.sub.2).sub.m (SO.sub.3 H).sub.2                  (I) 
    
     where n can vary from 1 to 2 and m can vary from 3 to 12. 
     The process for producing said salts consists of the following stages: (a) enriching the starting yeast with SAMe; (b) lysing the cells and recovering a solution rich is SAMe (cell lysate); (c) prepurifying the cell lysate by ultrafiltration; (d) passing the prepurified lysate through a column of weak acid ion exchange resin and eluting with the required disulphonic acid; (e) passing the eluate of said column through a column of absorption resin and washing with the required disulphonic acid; (f) concentrating the eluate of the latter column by reverse osmosis; (g) drying the concentrated solution.

This is a division of application Ser. No. 06/732,287, filed May 9,1985.

This invention relates to new stable sulpho-adenosyl-L-methionine (SAMe)salts.

More particularly, the invention relates to salts deriving from thereaction between SAMe and disulphonic acids, their production process,and pharamaceutical compositions which contain them as activeprinciples.

Said salts are particularly suitable for parenteral use.

SAMe is the main biological donor of methyl groups, and because of thischaracteristic it is of considerable interest both from the biologicalviewpoint and from the point of view of its therapeutic applications.

However, this product presents problems with regard to its large-scaleuse, these problems being connected with its thermal instability, evenat ambient temperature, and with the complexity of its preparation andpurification.

SAMe has therefore been the subject of numerous patents directed bothtowards the obtaining of new stable salts, and towards the provision ofpreparation processes which can be implemented on an industrial scale.

The present applicant has filed various patents relating both to newstable salts and to preparation methods for sulpho-adenosyl-L-methionine(Italian patents Nos. 1,043,885, 1,022,016, 1,022,036 and 1,054,175.Italian patent applications Nos. 23603A/81 and 22622A/83).

The salts discovered by the applicant as covered by the patentsmentioned heretofore are all very stable and are suitable forpharmaceutical use.

They have however the drawback of very high acidity (high strong acidequivalents per equivalent of SAMe) because of which in their injectableforms the lyophylised vial containing the active principle has to beaccompanied by a suitable buffer solvent which adjusts the pH of thefinal solutions to within physiological values.

The high saline concentration of the buffer therefore prevents the useof high product doses.

The main advantage of the new salts according to the present inventionis that they contain only 3 acid equivalents per equivalent of SAMe, andtherefore require a considerably smaller buffer quantity for theirneutralisation.

They are therefore particularly suitable for parental use of SAMe athigh dosage, which has proved to be required in clinical use for certainaffections.

Furthermore, the SAMe salts according to the present invention areindefinitely stable with time at a temperature up to 45° C., and aresoluble in water up to a concentration of at least 30% by weight, andare insoluble in common organic solvents.

Finally, said salts can be easily prepared economically on an industrialscale by means of a high-yield process.

The sulpho-adenosyl-L-methionine (SAMe) salts according to the presentinvention are characterised by the general formula:

    SAMe.n(CH.sub.2).sub.m (SO.sub.3 H).sub.2                  (I)

where n can vary from 1 to 2 and m can vary from 3 to 12.

The process for producing said salts, according to the presentinvention, is characterised by: (a) enriching the starting yeast withSAMe; (b) lysing the cells and recovering a solution rich in SAMe (celllysate); (c) prepurifying the cell lysate by ultrafiltration; (d)passing the prepurified lysate through a column of weak acid ionexchange resin and eluting with the required sulphonic acid; (e) passingthe eluate of said column through a column of absorption resin andwashing with the required sulphonic acid; (f) concentrating the eluateof the latter column by means of reverse osmosis; (g) drying theconcentrated solution.

These and further characteristics and advantages of the SAMe saltsaccording to the present invention will be more apparent from thedetailed description given hereinafter which relates particularly to theproduction process and is described for illustrative purposes.

The stages of the process for producing SAMe salts according to thepresent invention are conducted in the following manner:

(a) the starting yeast is enriched with SAMe by adding methionine tocultures of Saccharomyces cerevisiae, Torulopsis utilis, Candida utilisetc., in the manner described by Schlenk [Enzymologia, 29, 238 (1965)];

(b) cell lysis followed by recovery of a SAMe-rich aqueous solution(cell lysate): the lysis is effected by treating the enriched yeastfirstly with a solution of water and ethyl acetate in a volume ratio ofbetween 3:1 and 0.5:1 and preferably between 1.2:1 and 0.8:1; thequantity of the water-ethyl acetate solution used is preferably between1/20 and 1/2, and preferably between 1/4 and 1/5 of the moist cellweight, and the treatment is contained for a time of between 15 and 45minutes, and preferably 30 minutes. Sulphuric acid of between 0.1 N and0.5 N, and preferably 0.35 N, is then added in a quantity of between 1:1and 0.2:1 and preferably between 0.5:1 and 0.6:1 with respect to themoist cell weight. The treatment is continued for a time of between 1and 2 hours and preferably 1.5 hours at ambient temperature. The celllysis affected in this manner causes practically 100% of the SAMepresent to pass into solution. It should be noted that lysing the yeastcells with a mixture of organic solvent and dilute sulphuric acid isconsiderably more convenient than with perchloric acid at ambienttemperature or formic or acetic acid at 60° C. and the like, in that notonly does the lysis take place at ambient temperature, whichconsiderably favours SAMe stability, but is conducted under suchconditions that the solution can be easily filtered from the cellresidue, and contains none of the impurities which are present when theother lysis media are used, and which are difficult to remove by theknown preparation processes for pure SAMe;

(c) prepurification of the cell lysate by ultrafiltration: the celllysate originating from stage (b) is subjected to an ultra-filtrationprocess using membranes with a 10,000 nominal cut-off, which enable theprotein residues and high-molecular weight polysaccharide residues to beremoved from the lysate and which would otherwise fix on the ionexchange resins in the next stage, to progressively reduce theiractivity. The ultrafiltration process can be conducted either with flatmembranes or, preferably, with tubular membranes. It should be notedthat the use of ultrafiltration enables the resin column of the nextstage to be fed with a considerably more pure lysate, and in particularfree from high molecular-weight substances which by irreversibly fixingon to the resins would progressively poison them, so reducing theiractivity and thus their purification capacity. This pretreatmenttherefore considerably increases the average life of the resins in thecolumns, which would otherwise have to be frequently replaced because oftheir poisoning, and thus reduces production costs;

(d) passage of the prepurified lysate through a weak acid ion exchangeresin: the permeate originating from stage (c) is passed through acolumn of weak acid resin (COOH) in H⁺ form at a pH of between 3.5 and 7and preferably pH 5, at a rate of between 1 and 3 liquid volumes/hourper resin volume, and preferably a rate of 2 liquid volumes/hour perresin volume. The quantity of resin used is in the region of 10-50, andpreferably 30, liters per kg of SAMe. The lysate is passed through thecolumn, which is then washed with distilled water, and then with 0.1 Macetic acid until the eluate has a pH of less than 3, and then withdistilled water, and finally the SAMe is eluted with a 0.2 N solution ofthe required disulphonic acid. The eluate containing the SAMe containssmall quantities of coloured impurities and between 3% and 10% of5'-deoxy-5'-methyl-thioadenosine (the main SAMe degradation product).These impurities are removed by using absorption resins (stage e);

(e) passage of the eluate from the preceding column through anabsorption column, and washing with the required sulphonic acid; it hasbeen unexpectedly found that absorption polymers of polystyrene andacrylic ester such as those identified by the tradenames Amberlite XAD2,Amberlite XAD4 or Amberlite XAD7 type, when in a strongly acid solutionsuch as the eluate from the preceding column (stage d), retainpractically no SAMe whereas they are able to easily adsorb colouredimpurities, adenine and 5'-deoxy-5-methylthioadenosine. Stage (e) iseffected by passing the eluate from stage (d) through a column of one ofthe aforesaid resins, preferably Amberlite XAD4, at a rate of between0.2 and 1 liquid volume/hour per resin volume, and preferably 0.5 liquidvolumes/hour per resin volume. The resin quantity used is in the regionof 10-50, preferably 30, liters/kg of SAMe. The SAMe solution is passedthrough the column, which is then washed with a 20 mN solution of therequired disulphonic acid until SAMe disappears from the eluate. Theeluate, containing about 10 g/l of very pure SAMe, is fed to thesubsequent concentration stage (f). It should be noted that the colouredimpurities are removed in the known art by using activated carbons,which although on the one hand are effective in removing this type ofimpurity, on the other hand irreversibly absorb a considerable quantityof SAMe (about 15% of the weight of the carbon used), thus leading to aconsiderable yield reduction. The advantage of absorption resins thusconsists of the fact that the same degree of purification is obtained,but with a considerably higher yield than when using activated carbon;

(f) concentration of the eluate of stage (e) by means of reverseosmosis: stage (f) is affected by subjecting the eluate from stage (e)to a reverse osmosis process using desalination membranes of high NaClrejection, which are able to practically completely retain the SAMe,while allowing water and part of the disulphonic acid to pass aspermeate. Polyamide membranes are preferably used because of their highstrength in strongly acid solution. Concentration by reverse osmosisenables the eluate from stage (e) to be concentrated from 10 g/l,100-150 g/l, and preferably to 120 g/l. The SAMe solution concentratedby reverse osmosis is analysed to determine the SAMe and disulphonicacid concentrations. A suitable quantity of disulphonic acid is added inorder to obtain the required stoichiometric composition (preferably 3acid equivalents per SAMe equivalent). This solution is fed to thesubsequent drying stage (g) which uses a spray dryer to obtain the finalproduct;

(g) drying of the concentrated solution: in this stage, the product isatomised in a drying chamber fed with hot air. The concentration of theinlet solution (expressed as SAMe) is between 100 and 200 g/l, andpreferably 120 g/l. The feed temperature of the drying air, which haspreferably been previously dehumidified, is between 140° and 200° C.,and preferably 160° C. The outlet air temperature is preferably between40° and 100° C., and preferably 60° C. Under these conditions, theoutlet product has a temperature of between 40° and 60° C., and iscooled to ambient temperature by means of dehumidified air. Preferably,the plant operates with a suitable device for continuously extractingthe dry product. It should be noted that the use of the spray dryer forthe final product drying, compared with previously known methods such aslyophilisation, results in a considerable cost reduction and is moreeasily implemented on a large production scale.

The disulphonic SAMe salifying acids which are used for elution in thecolumn comprising weak acid ion exchange resin (stage d) can be eitherobtained commercially or easily prepared in the form of disodium saltsfrom the corresponding dibromides by reaction with sodium sulphite inaccordance with the equation:

    (CH.sub.2).sub.m (Br).sub.2 +2Na.sub.2 SO.sub.3 →(CH.sub.2).sub.m (SO.sub.3 Na).sub.2 +2NaBr

where m can vary from 3 to 13.

The reaction is conducted under reflux in a water-alcohol mixturecontaining preferably 7.5 parts of water, 2 parts of 95% ethanol and 0.5parts n-butanol, preferably for 3 days.

1 mole of alkyl dibromide as heretofore defined is suspended in 1 literof water-alcohol mixture as heretofore defined, 2.2 moles of anhydroussodium sulphite are added, and the mixture heated under reflux for 3days.

On termination of the reaction the alcohols are removed by distillation,the aqueous solution is concentrated to a volume of between 0.5 and 1liter, and the sulphonic acid disodium salt is allowed to crystalliseunder cold conditions (4° C.).

It is recrystallised from an equal volume of water, and the product isfiltered off and dried under vacuum. The average yield of disodium saltis 90 mol %.

The disodium salt is redissolved in water of such a quantity as toobtain a 0.3 N solution, and the solution obtained is fed through acolumn of strong acid ion exchange resin (Amberlite IR 120 or Dowex 50type) is H⁺ form, which has been carefully activated and washed. Theresin retains the sodium, and a solution of disulphonic acid is obtainedat the column outlet.

The column is washed with distilled water to pH 4, the eluate istitrated and is diluted to obtain a 0.2 N solution of disulphonic acid.

This solution is used in stages (d) and (e) of the SAMe production.

Non-limiting illustrative examples are given hereinafter of the processfor producing the new stable SAMe salts of disulphonic acids accordingto the present invention, and of pharmaceutical compositions of saidsalts.

EXAMPLE 1 Preparation of 0.2 N Solutions of Disulphonic Acids of GeneralFormula (CH₂)_(m) (SO₃ H)₂

75 liters of distilled water, 20 liters of 95% ethanol and 5 liters ofn-butanol are added to 21.6 kg (100 moles) of 1,4-dibromo butane. 26.46kg (210 moles) of anhydrous sodium sulphite are added, and the mixtureheated under reflux for 3 days.

On termination of the reaction, 20 liters of distilled water are added,and the mixture distilled until the alcohols are completely removed.

The mixture is diluted to a final volume of 60 liters with water andheated until complete dissolution has occurred.

The disodium of the 1,4-butanedisulphonic acid obtained is allowed tocrystallise overnight at 4° C.

The product is filtered off and washed with 10 liters of water.

The mother liquors are concentrated under vaccum to a volume of 20liters, and left to crystallise overnight at 4° C.

The product is filtered off and washed with 4 liters of water.

The crystalline mass from the two filtrations is resuspended in 50liters of water and dissolved under hot conditions.

The solution is allowed to crystallise overnight at 4 ° C.

The product is filtered off and washed with 5 liters of water. Thebutanedisulphonic acid sodium salt is dried under vacuum.

A further product fraction is obtained by concentrating the motherliquors to 10 liters, and leaving this to crystallise overnight at 4°C., then filtering off the product and drying it under vacuum.

In this manner 25.2 kg of 1,4-butanedisulphonic acid disodium saltmonohydrate are obtained (90 moles, 90% molar yield).

The product was identified by elementary analysis and corresponds to theformula C₄ H₈ O₆ S₂ Na₂.H₂ O:

    ______________________________________                                                  % C        % H    % S                                               ______________________________________                                        Calculated  17.1         3.6    22.9                                          Found       17.1         3.7    22.9                                          ______________________________________                                    

A column was prepared containing 200 liters of Amberlite IR 120 resinpreviously activated with 6M HCl until the disappearance of the Na⁺ ionfrom the eluate, and washed with distilled water until the Cl⁻ iondisappeared from the eluate.

25.2 kg of 1,4-butanedisulphonic acid disodium salt monohydrate aredissolved in 300 liters of water and fed to the head of the column. Theeluate containing the 1,4-butanedisulphonic acid is collected, and thecolumn is washed with water until the pH of the eluate has reached 4.

It is diluted to a final volume of 900 liters to obtain a 0.2 M solutionof 1,4-butanedisulphonic acid, which is used as such for the preparationof the corresponding SAMe salt.

Operating in an analogous manner but using 20.2 kg of1,3-dibromo-propane as starting material, 900 liters of a 0.2 N solutionof 1,3-propanedisulphonic acid are obtained.

Using 23 kg of 1,5-dibromopentane, 900 liters of 0.2 N solution of1,5-pentanedisulphonic acid are obtained.

Using 24.4 kg of 1,5-dibromohexane, 900 liters of 0.2 N solution of1,6-hexanedisulphonic acid are obtained.

Using 27.2 kg of 1,8-dibromooctane, 900 liters of a 0.2 N solution of1,8-octanedisulphonic acid are obtained.

Finally, using 30 kg of 1,10-dibromodecane, 900 liters of a 0.2 Nsolution of 1,10-decanedisulphonic acid are obtained.

EXAMPLE 2 Preparation of the SAlt SAMe.1.5 (1,4-Butanedisulphonate)

220 liters of ethyl acetate and 220 liters of water are added at ambienttemperature to 1800 kg of yeast enriched with SAMe (6.88 g/kg) inaccordance with Schlenk [Enzymologia 29, 283 (1965)].

After energetic agitation for 30 minutes, 1000 liters of 0.35 Nsulphuric acid are added, and agitation is continued for a further 11/2hours.

The mixture is filtered through a rotary filter, which is washed withwater to obtain 2800 liters of solution containing 4.40 g/l of SAMe,equal to 99.5% of that present in the starting material.

The SAMe solution obtained in this manner (pH 2.5) is fed to anultrafiltration plant using tubular membranes with a 10,000 cut-off.

The permeate leaving the membrane is collected in a suitable vessel,whereas the concentrate is continuously recycled to a final volume of200 liters. At this point, distilled water is added and recycling iscontinued until the SAMe is completely extracted.

3500 liters of ultrafiltered lysate are obtained, which is adjusted topH 5 by adding 2N NaOH.

A column is prepared containing 400 liters of Amberlite CG 50 resin inH⁺ form, which has been carefully washed with distilled water.

The lysate is passed through the resin column at a rate of 800 1/h, keptconstant during the entire procedure.

400 liters of distilled water, 3200 liters of 0.1 M acetic acid, and 400liters of distilled water are then passed through in succession.

The SAMe is eluted with 800 liters of 0.2N 1,4-butanedisulphonic acid.The 800 liters of eluate obtained in this manner contain approximately10 kg of SAMe.

A column is prepared containing 400 liters of Amberlite XAD4 resin whichhad been previously activated with 800 liters of 0.1N NaOH and 800liters of 0.1N H₂ SO₄, and then carefully washed with distilled water.

The previously obtained SAMe solution is passed through the column at arate of 200 1/h, kept constant during the entire procedure.

400 liters of 20 mN 1,4-butanedisulphonic acid are then passed through.

The eluate containing the SAMe (about 1000 containing 10 kg of SAMe) iscollected.

The solution obtained in this manner is fed to a reverse osmosis plantof the flat type using polyamide desalination membranes.

In this plant, the SAMe solution is concentrated to 80 liters containing9.9 kg of SAMe.

5 liters of a 2N solution of butanedisulphonic acid are added.

The solution obtained in this manner is fed to a spray drying plant fedwith air at 160° C.

The dry product is continuously extracted from the plant.

18 kg of powdery product are obtained, having the following compositionon analysis:

    ______________________________________                                        SAMe                54.9%                                                     1,4-butanedisulphonic acid                                                                        44.9%                                                     H.sub.2 O            0.2%                                                     ______________________________________                                    

corresponding to the salt SAMe.1.5 (1,4-butanedisulphonate).

The product is in the form of a crystalline white powder white powdersoluble in water to 30% by weight with the formation of a colourlesssolution, and insoluble in common organic solvents.

Using thin layer chromatography in accordance with Anal. Biochem. 4,16-28 (1971), the product is found to be free from any impurity.

    ______________________________________                                        Elementary analysis:                                                          C.sub.15 H.sub.22 N.sub.6 O.sub.5 S.1.5 C.sub.4 H.sub.10 O.sub.6 S.sub.2                % N        % C    % H                                               ______________________________________                                        Calculated  11.6         34.7   5.1                                           Found       11.5         34.8   5.1                                           ______________________________________                                    

The ultraviolet spectrum for the product shows an absorption maximum (inbuffer of pH 4) at 258.5 nm, with E_(1%) =193.

EXAMPLE 3 Preparation of the Salt SAMe1.5 (1,3-Propanedisulphonate)

The procedure of Example 2 is followed, but using1,3-propane-disulphonic acid instead of 1,4-butanedisulphonic acid.

17.45 kg of powder are obtained which on analysis shows the followingcomposition:

    ______________________________________                                        SAMe                56.5%                                                     1,3-prepanedisulphonic acid                                                                       43.3%                                                     H.sub.2 O            0.2%                                                     ______________________________________                                    

corresponding to the salt SAMe.1.5 (1,3-propanedisulphonate).

The product is in the form of a crystalline white powder soluble inwater to 30% by weight with the formation of a colourless solution, andinsoluble in common organic solvents.

Thin layer chromatography in accordance with Anal. Biochem. 4, 16-28(1971) shows that the product is free from any impurity.

    ______________________________________                                        Elementary analysis:                                                          C.sub.15 H.sub.22 N.sub.6 O.sub.5 S.1.5 C.sub.3 H.sub.8 O.sub.6 S.sub.2                 % N        % C    % H                                               ______________________________________                                        Calculated  11.9         33.2   4.8                                           Found       11.9         33.1   4.8                                           ______________________________________                                    

The ultraviolet spectrum for the product shows an absorption maximum (inbuffer of pH 4) at 258.5 nm with E_(1%) =199.

EXAMPLE 4 Preparation of the Salt SAMe.1.5 (1,5-Pentanedisulphonate)

The procedure of Example 2 is followed, but 1,5-pentanedisulphonic acidis used in place of the 1,4-butanedisulphonic acid.

18.5 kg of powder are obtained which on analysis shows the followingcomposition:

    ______________________________________                                        SAMe                53.3%                                                     1,5-pentanedisulphonic acid                                                                       46.5%                                                     H.sub.2 O            0.2%                                                     ______________________________________                                    

corresponding to the salt SAMe.1.5 (1,5-pentanedisulphonate).

The product is in the form of a crystalline white powder soluble inwater to 30% by weight with the formation of a colourless solution, andinsoluble in common organic solvents.

This layer chromatography in accordance with Anal. Biochem. 4, 16-28(1971) shows the product is free from any impurity.

    ______________________________________                                        Elementary analysis:                                                          C.sub.15 H.sub.22 N.sub.6 O.sub.5 S.1.5 C.sub.5 H.sub.12 O.sub.6 S.sub.2                % N        % C    % H                                               ______________________________________                                        Calculated  11.3         36.2   5.4                                           Found       11.4         36.2   5.3                                           ______________________________________                                    

The ultraviolet spectrum for the product (in buffer of pH 4) shows anabsorption maximum at 258.5 nm with E_(1%) =188.

EXAMPLE 5 Preparation of the Salt SAMe.1.5 (1,6-Hexanedisulphonate)

The procedure of Example 2 is followed, but 1,6-hexanedisulphonic acidis used in place of the 1,4-butanedisulphonic acid.

19 kg of powder are obtained which on analysis shows the followingcomposition:

    ______________________________________                                        SAMe                51.8%                                                     1,6-hexanedisulphonic acid                                                                        48%                                                       H.sub.2 O            0.2%                                                     ______________________________________                                    

corresponding to the salt SAMe.1.5 (1,6-hexanedisulphonate).

The product is in the form of a crystalline white powder soluble inwater to 30% by weight with the formation of a colourless solution, andinsoluble in common organic solvents.

This layer chromatography in accordance with Anal. Biochem. 4, 16-28(1971) shows that the product is free from any impurity.

    ______________________________________                                        Elementary analysis:                                                          C.sub.15 H.sub.22 N.sub.6 O.sub.5 S.1.5 C.sub.6 M.sub.14 O.sub.6 S.sub.2                % N        % C    % M                                               ______________________________________                                        Calculated  10.9         37.6   5.6                                           Found       10.8         37.5   5.6                                           ______________________________________                                    

The ultraviolet spectrum for the product (in buffer of pH 4) shows anabsorption maximum at 258.5 nm with E_(1%) =182.

EXAMPLE 6 Preparation of the Salt SAMe.1.5 (1,8-Octanedisulphonate)

The procedure of Example 2 is followed, but 1,8-octanedisulphonic acidis used in place of the 1,4-butanedisulphonic acid. 20 kg of powder areobtained, which on analysis shows the following composition:

    ______________________________________                                        SAMe                49.3%                                                     1,8-octanedisulphonic acid                                                                        50.5%                                                     H.sub.2 O            0.2%                                                     ______________________________________                                    

corresponding to the salt SAMe.1.5 (1,8-octanedisulphonate).

The product is in the form of a crystalline white powder soluble inwater to 30% with the formation of a colourless solution, and insolublein common organic solvents.

Thin layer chromatography in accordance with Anal. Biochem. 4, 16-28(1971) shows that the product is free from any impurity.

    ______________________________________                                        Elementary analysis:                                                          C.sub.15 H.sub.22 N.sub.6 O.sub.5 S.1.5 C.sub.8 H.sub.18 O.sub.6 S.sub.2                % N        % C    % H                                               ______________________________________                                        Calculated  10.4         40.0   6.0                                           Found       10.4         39.9   5.9                                           ______________________________________                                    

The ultraviolet spectrum for the product (in buffer of pH 4) shows anabsorption maximum at 258.5 nm with E_(1%) =173.

EXAMPLE 7 Preparation of the Salt SAMe.1.5 (1,10-Decanedisulphonate)

The procedure of Example 2 is followed, but 1,10-decanedisulphonic acidis used in place of the 1,4-butanedisulphonic acid.

21 kg of powder are obtained which on analysis shows the followingcomposition:

    ______________________________________                                        SAMe                46.8%                                                     1,10-decanedisulphonic acid                                                                       53%                                                       H.sub.2 O            0.2%                                                     ______________________________________                                    

corresponding to the salt SAMe.1.5 (1,10-decanedisulphonate).

The product is in the form of a crystalline white powder soluble inwater to 20% by weight with the formation of a colourless solution, andinsoluble in common organic solvents.

Thin layer chromatography in accordance with Anal. Biochem. 4, 16-28(1971) shows the product is free from any impurity.

    ______________________________________                                        Elementary analysis:                                                          C.sub.15 H.sub.22 N.sub.6 O.sub.5 S.1.5 C.sub.10 H.sub.22 O.sub.6             S.sub.2                                                                                 % N        % C    % H                                               ______________________________________                                        Calculated  9.8          42.3   6.5                                           Found       9.9          42.4   6.5                                           ______________________________________                                    

The ultraviolet spectrum for the product (in buffer of pH 4) shows anabsorption maximum at 258.5 nm with E_(1%) =164.

EXAMPLE 8 Injectable Pharmaceutical Compositions ContainingS-Adenosyl-L-Methionine Salts of Disulphonic Acids, with Lysine as theBuffer Agent.

(a) a lyophilised vial contains:

    ______________________________________                                        SAMe.1.5 (1,4-butanedisulphonate)                                                                      364    mg                                            equivalent to SAMe ion   200    mg                                            a solvent vial contains:                                                      Lysine base              150    mg                                            Water for injectable solutions                                                                         3      ml                                            quantity to make up to                                                        ______________________________________                                    

(b) a lyophilised vial contains:

    ______________________________________                                        SAMe.1.5 (1,4-butanedisulphonate)                                                                      729    mg                                            equivalent to SAMe ion   400    mg                                            a solvent vial contains:                                                      Lysine base              300    mg                                            Water for injectable solutions                                                                         5      ml                                            quantity to make up to                                                        ______________________________________                                    

(c) a lyophilised vial contains:

    ______________________________________                                        SAMe.1.5 (1,4-butanedisulphonate)                                                                      1821   mg                                            equivalent to SAMe ion   1000   mg                                            a solvent vial contains:                                                      Lysine base              750    mg                                            Water for injectable solutions                                                                         10     ml                                            quantity to make up to                                                        ______________________________________                                    

I claim:
 1. Stable sulpho-adenosyl-L-methionine (SAMe) saltscharacterised by the general formula:

    SAMe.n(CH.sub.2).sub.m (SO.sub.3 H).sub.2                  (I)

where n can vary between the limits of 1 and 2 inclusive and m can varyfrom 3 to
 12. 2. Pharmaceutical compositions for parenteral usecomprising, as active principle, SAMe salts of formula:

    SAMe.n(CH.sub.2).sub.m (SO.sub.3 H).sub.2                  (I)

where n can vary between the limits of 1 and 2 inclusive, and m is awhole number between 3 and 12 and a pharmaceutically acceptable carrier.